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European Journal of Nuclear Medicine and Molecular Imaging

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01.01.2013 | Original Article

PET imaging of the brain serotonin transporters (SERT) with N,N-dimethyl-2-(2-amino-4-[¹⁸F]fluorophenylthio)benzylamine (4-[¹⁸F]-ADAM) in humans: a preliminary study

verfasst von: Wen-Sheng Huang, San-Yuan Huang, Pei-Shen Ho, Kuo-Hsing Ma, Ya-Yao Huang, Chin-Bin Yeh, Ren-Syuan Liu, Cheng-Yi Cheng, Chyng-Yann Shiue

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 1/2013

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Abstract

Purpose

The aim of this study was to assess the feasibility of using 4-[¹⁸F]-ADAM as a brain SERT imaging agent in humans.

Methods

Enrolled in the study were 19 healthy Taiwanese subjects (11 men, 8 women; age 33 ± 9 years). The PET data were semiquantitatively analyzed and expressed as specific uptake ratios (SUR) and distribution volume ratios (DVR) using the software package PMOD. The SUR and DVR of 4-[¹⁸F]-ADAM in the raphe nucleus (RN), midbrain (MB), thalamus (TH), striatum (STR) and prefrontal cortex (PFC) were determined using the cerebellum (CB) as the reference region.

Results

4-[¹⁸F]-ADAM bound to known SERT-rich regions in human brain. The order of the regional brain uptake was MB (RN) > TH > STR > PFC > CB. The DVR (n = 4, t* = 60 min) in the RN, TH, STR and PFC were 3.00 ± 0.50, 2.25 ± 0.45, 2.05 ± 0.31 and 1.40 ± 0.13, respectively. The optimal time for imaging brain SERT with 4-[¹⁸F]-ADAM was 120–140 min after injection. At the optimal imaging time, the SURs (n = 15) in the MB, TH, STR, and PFC were 2.25 ± 0.20, 2.28 ± 0.20, 2.12 ± 0.18 and 1.47 ± 0.14, respectively. There were no significant differences in SERT availability between men and women (p < 0.05).

Conclusion

The results of this study showed that 4-[¹⁸F]-ADAM was safe for human studies and its distribution in human brain appeared to correlate well with the known distribution of SERT in the human brain. In addition, it had high specific binding and a reasonable optimal time for imaging brain SERT in humans. Thus, 4-[¹⁸F]-ADAM may be feasible for assessing the status of brain SERT in humans.

Kish SJ. How strong is the evidence that brain serotonin neurons are damaged in human users of ecstasy? Pharmacol Biochem Behav. 2002;71:845–55.PubMedCrossRef

Siegel A, Roeling TA, Gregg TR, Kruk MR. Neuropharmacology of brain-stimulation-evoked aggression. Neurosci Biobehav Rev. 1999;23:359–89.PubMedCrossRef

Mann J. Role of the serotonergic system in the pathogenesis of major depression and suicidal behavior. Neuropsychopharmacology. 1999;21:99S–105.PubMed

Meltzer C, Smith G, DeKosky S, et al. Serotonin in aging, late-life depression, and Alzheimer’s disease: the emerging role of functional imaging. Neuropsychopharmacology. 1998;18:407–30.PubMedCrossRef

Jovanovic H, Lundberg J, Karlsson P, et al. Sex differences in the serotonin 1A receptor and serotonin transporter binding in the human brain measured by PET. Neuroimage. 2008;39:1408–19.PubMedCrossRef

Pacher P, Kecskemeti V. Trends in the development of new antidepressants. Is there a light at the end of the tunnel? Curr Med Chem. 2004;11:925–43.PubMedCrossRef

Brust P, Hesse S, Muller U, Szabo Z. Neuroimaging of the serotonin transporter: possibilities and pitfalls. Curr Psychiatry Rev. 2006;2:111–49.CrossRef

Meyer J. Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. J Psychiatry Neurosci. 2007;32:86–102.PubMed

Smith D, Jakobsen S. Molecular tools for assessing human depression by positron emission tomography. Eur Neuropsychopharmacol. 2009;19:611–28.PubMedCrossRef

10.

Suehiro M, Ravert HT, Dannals RF, Scheffel U, Wagner Jr HN. Synthesis of a radiotracer for studying serotonin uptake sites with positron emission tomography: [11C]McN–5652–Z. J Labelled Cpd Radiopharm. 1992;31:841–8.CrossRef

11.

Buck A, Gucker PM, Schönbächler RD, et al. Evaluation of serotonergic transporters using PET and [11C](+)McN-5652: assessment of methods. J Cereb Blood Flow Metab. 2000;20:253–62.PubMedCrossRef

12.

Suehiro M, Greenberg J, Shiue C, Gonzalez C, Dembowski B, Reivich M. Radiosynthesis and biodistribution of the S-[18F]fluoroethyl analog of McN5652. Nucl Med Biol. 1996;23(4):407–12.PubMedCrossRef

13.

Zessin J, Eskola O, Brust P, et al. Synthesis of S-([18F] fluoromethyl)-(+)-McN5652 as a potential PET radioligand for the serotonin transporter. Nucl Med Biol. 2001;28(7):857–63.PubMedCrossRef

14.

Hesse S, Brust P, Mäding P, et al. Imaging of the brain serotonin transporters (SERT) with 18F-labelled fluoromethyl-McN5652 and PET in humans. Eur J Nucl Med Mol Imaging. 2012;39(6):1001–11.PubMedCrossRef

15.

Wilson AA, Ginovart N, Schmidt M, Meyer JH, Threlkeld PG, Houle S. Novel radiotracers for imaging the serotonin transporter by positron emission tomography: synthesis, radiosynthesis, and in vitro and ex vivo evaluation of 11C-labeled 2-(phenylthio) araalkylamines. J Med Chem. 2000;43:3103–10.PubMedCrossRef

16.

Huang Y, Hwang D, Bae S, et al. A new positron emission tomography imaging agent for the serotonin transporter: synthesis, pharmacological characterization, and kinetic analysis of [11C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine ([11C]AFM). Nucl Med Biol. 2004;31:543–56.PubMedCrossRef

17.

Tarkiainen J, Vercouillie J, Emond P, et al. Carbon–11 labelling of MADAM in two different positions: a highly selective PET radioligand for the serotonin transporter. J Labelled Cpd Radiopharm. 2001;44:1013–23.CrossRef

18.

Jarkas N, Votaw JR, Voll RJ, et al. Carbon-11 HOMADAM: a novel PET radiotracer for imaging serotonin transporters. Nucl Med Biol. 2005;32:211–24.PubMedCrossRef

19.

Ginovart N, Wilson AA, Meyer JH, Hussey D, Houle S. Positron emission tomography quantification of [11C]-DASB binding to the human serotonin transporter: modeling strategies. J Cereb Blood Flow Metab. 2001;21:1342–53.PubMedCrossRef

20.

Nye JA, Votaw JR, Jarkas N, et al. Compartmental modeling of 11C-HOMADAM binding to the serotonin transporter in the healthy human brain. J Nucl Med. 2008;49:2018–25.PubMedCrossRef

21.

Nabulsi N, Williams W, Planeta-Wilson B, et al. The serotonin transporter tracer [11C]AFM provides high specific binding signals in humans. J Nucl Med. 2008;49:80.

22.

Lundberg J, Odano I, Olsson H, Halldin C, Farde L. Quantification of 11C-MADAM binding to the serotonin transporter in the human brain. J Nucl Med. 2005;46:1505–15.PubMed

23.

Oya S, Choi SR, Coenen H, Kung HF. New PET imaging agent for the serotonin transporter: [(18)F]ACF (2-[(2-amino-4-chloro-5-fluorophenyl)thio]-N,N-dimethyl-benzenmethanamine). J Med Chem. 2002;45:4716–23PubMedCrossRef

24.

Shiue GG, Fang P, Shiue CY. Synthesis of N,N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio) benzylamine as a serotonin transporter imaging agent. Appl Radiat Isot. 2003;58:183–91.PubMedCrossRef

25.

Peng CJ, Huang YY, Huang WS, Shiue CY. An automated synthesis of N,N-dimethyl-2-(2-amino-4-[18F] fluorophenylthio) benzylamine (4-[18F]-ADAM) for imaging serotonin transporters. Appl Radiat Isot. 2008;66:625–31.PubMedCrossRef

26.

Huang YY, Huang WS, Chu TC, Shiue CY. An improved synthesis of 4-[18F]-ADAM, a potent serotonin transporter imaging agent. Appl Radiat Isot. 2009;67:1063–7.PubMedCrossRef

27.

Fang P, Shiue GG, Shimazu T, Greenberg JH, Shiue CY. Synthesis and evaluation of N,N-dimethyl-2-(2-amino-5-[18F]fluorophenylthio)benzylamine as a serotonin transporter imaging agent. Appl Radiat Isot. 2004;61:1247–54.PubMedCrossRef

28.

Huang Y, Bae SA, Zhu Z, Guo N, Roth BL, Laruelle M. Fluorinated diaryl sulfides as serotonin transporter ligands: synthesis, structure-activity relationship study, and in vivo evaluation of fluorine-18-labeled compounds as PET imaging agents. J Med Chem. 2005;48:2559–70.PubMedCrossRef

29.

Parhi AK, Wang JL, Oya S, Choi SR, Kung MP, Kung HF. 2-(2′-((Dimethylamino) methyl)-4′-(fluoroalkoxy)-phenylthio)benzenamine derivatives as serotonin transporter imaging agents. J Med Chem. 2007;50:6673–84.PubMedCrossRef

30.

Garg S, Thopate S, Minton R, Kimberly W, Lynch A, Garg P. 3-Amino-4-(2-((4-[18F]fluorobenzyl)methylamino)methylphenylsulfanyl)benzonitrile, an F-18 fluorobenzyl analogue of DASB: synthesis, in vitro binding, and in vivo biodistribution studies. Bioconjug Chem. 2007;18(5):1612–8.PubMedCrossRef

31.

Wang JL, Parhi AK, Oya S, Lieberman B, Kung MP, Kung HF. 2-(2′-((Dimethylamino)methyl)-4′-(3-[(18)F]fluoropropoxy)-phenylthio)benzenamine for positron emission tomography imaging of serotonin transporters. Nucl Med Biol. 2008;35:447–58.PubMedCrossRef

32.

Shiue GG, Choi SR, Fang P, et al. N,N-Dimethyl-2-(2-amino-4-18F-fluorophenylthio)-benzylamine (4-18F-ADAM): an improved PET radioligand for serotonin transporters. J Nucl Med. 2003;44:1890–7.PubMed

33.

Ma KH, Huang WS, Kuo YY, et al. Validation of 4-[18F]-ADAM as a SERT imaging agent using micro-PET and autoradiography. Neuroimage. 2009;45:687–93.PubMedCrossRef

34.

Chen YA, Huang WS, Lin YS, et al. Characterization of 4-[18F]-ADAM as an imaging agent for SERT in non-human primate brain using PET: a dynamic study. Nucl Med Biol. 2012;39:279–85.PubMedCrossRef

35.

Huang YY, Ma KH, Tseng TW, et al. Biodistribution, toxicity and radiation dosimetry studies of the serotonin transporter radioligand 4-[18F]-ADAM in rats and monkeys. Eur J Nucl Med Mol Imaging. 2010;37:545–55.PubMedCrossRef

36.

Huang W, Huang S, Yeh C, et al. 18F-ADAM PET in healthy and drug-naive depressant subjects. J Nucl Med. 2007;48:261P.

37.

Varrone A, Asenbaum S, Borght TV, et al. EANM procedure guidelines for PET brain imaging using [18F]FDG, version 2. Eur J Nucl Med Mol Imaging. 2009;36:2103–10.PubMedCrossRef

38.

Kish SJ, Furukawa Y, Chang LJ, et al. Regional distribution of serotonin transporter protein in postmortem human brain: is the cerebellum a SERT-free brain region? Nucl Med Biol. 2005;32:123–8.PubMedCrossRef

39.

Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab. 1996;16:834–40.PubMedCrossRef

40.

Huang SC, Truong D, Wu HM, et al. An internet-based "kinetic imaging system" (KIS) for MicroPET. Mol Imaging Biol. 2005;7:330–41.PubMedCrossRef

41.

Laruelle M, Vanisberg M, Maloteaux J. Regional and subcellular localization in human brain of [3H]paroxetine binding, a marker of serotonin uptake sites. Biol Psychiatry. 1988;24:299–309.PubMedCrossRef

42.

Owens MJ, Nemeroff CB. Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem. 1994;40:288–95.PubMed

43.

Rosel P, Menchon J, Oros M, et al. Regional distribution of specific high affinity binding sites for 3H-imipramine and 3H-paroxetine in human brain. J Neural Transm. 1997;104:89–96.PubMedCrossRef

44.

Logan J. Strategies for quantifying PET imaging data from tracer studies of brain receptors and enzymes. In: Welch MJ, Redvanly CS, editors. Handbook of radiopharmaceuticals. New York: Wiley Online Library; 2003. p. 501–27.

45.

Huang Y, Narendran R, Bae S, et al. A PET imaging agent with fast kinetics: synthesis and in vivo evaluation of the serotonin transporter ligand [11C]2-[2-dimethylaminomethylphenylthio)]-5-fluorophenylamine ([11C]AFA). Nucl Med Biol. 2004;31:727–38.PubMedCrossRef

46.

Huang Y, Bae SA, Zhu Z, et al. [18F]AFM is a specific PET radiotracer for the serotonin transporters: comparison with [11C]AFM. Neuroimage. 2002;16:S2.

47.

Naganawa M, Planeta-Wilson B, Nabulsi N, et al. Quantification of serotonin transporters with [11C]AFM: evaluation of reference region methods. Neuroimage. 2008;41:T28.CrossRef

48.

Huang Y, Hwang DR, Narendran R, et al. Comparative evaluation in nonhuman primates of five PET radiotracers for imaging the serotonin transporters: [11C]McN 5652, [11C]ADAM, [11C]DASB, [11C]DAPA, and [11C]AFM. J Cereb Blood Flow Metab. 2002;22:1377–98.PubMedCrossRef

49.

Halldin C, Lundberg J, Sóvágó J, et al. [11C]MADAM, a new serotonin transporter radioligand characterized in the monkey brain by PET. Synapse. 2005;58:173–83.PubMedCrossRef

50.

Chou YH, Yang BH, Chung MY, et al. Imaging the serotonin transporter using 123I-ADAM in the human brain. Psychiatry Res. 2009;172:38–43.PubMedCrossRef

51.

Chou YH, Halldin C, Farde L. Clozapine binds preferentially to cortical D1-like dopamine receptors in the primate brain: a PET study. Psychopharmacology. 2006;185:29–35.PubMedCrossRef

52.

Staley JK, Krishnan-Sarin S, Zoghbi S, et al. Sex differences in [123I]beta-CIT SPECT measures of dopamine and serotonin transporter availability in healthy smokers and nonsmokers. Synapse. 2001;41:275–84.PubMedCrossRef

53.

Ho P, Ho K, Huang W, Yen C, Shih M, Shen L, Ma K, Huang S. Association study of serotonin transporter availability and SLC6A4 gene polymorphisms in patients with major depression. Psychiatry Res. 2012: in press.

54.

Herold N, Uebelhack K, Franke L, et al. Imaging of serotonin transporters and its blockade by citalopram in patients with major depression using a novel SPECT ligand [123I]-ADAM. J Neural Transm. 2006;113:659–70.PubMedCrossRef

55.

Joensuu M, Tolmunen T, Saarinen PI, et al. Reduced midbrain serotonin transporter availability in drug-naive patients with depression measured by SERT-specific [123I] nor-beta-CIT SPECT imaging. Psychiatry Res. 2007;154:125–31.PubMedCrossRef

Titel: PET imaging of the brain serotonin transporters (SERT) with N,N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio)benzylamine (4-[18F]-ADAM) in humans: a preliminary study
verfasst von: Wen-Sheng Huang
San-Yuan Huang
Pei-Shen Ho
Kuo-Hsing Ma
Ya-Yao Huang
Chin-Bin Yeh
Ren-Syuan Liu
Cheng-Yi Cheng
Chyng-Yann Shiue
Publikationsdatum: 01.01.2013
Verlag: Springer-Verlag
Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 1/2013
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-012-2250-5

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusion

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